Loperamide is an opiate agonist used for the treatment of diarrhea; see "5396. Loperamide", The Merck Index, Tenth Edition, M. Windholz, ed., p. 797; and Physicians' Desk Reference for Nonprescription Drugs, 11th Ed. (1990), E. R. Barnhart, pub., pp. 593-594. Loperamide is one of a class of compounds disclosed in U.S. Pat. No. 3,714,159 issued to Janssen, Niemegeers, Stokbroekx & Vandenberk on Jan. 30, 1973. Lomeramide N-oxide is disclosed in "Drug Compendium", Comprehensive Medicinal Chemistry, Vol. 6 (1990), C. Hansch, P. G. Sammes, J. B. Taylor & C. J. Drayton, eds., Pergamon Press, N.Y., p. 629, and in Niemegeers, C. J. E., F. Awouters, F. M. Lenaerts, K. S. K. Artois & J. Vermeire, "Antidiarrheal Specificity and Safety of the N-Oxide of Loperamide (R 58 425) in Rats", Drug Development Research, Vol. 8 (1986), pp. 279-286. The above references are hereby incorporated herein by reference.
Loperamide is similar to other opiate agonists in having binding affinities at mu and delta opiate receptors. See, e.g., Mackerer, C. R., G. A. Clay & E. Z. Dajani, "Loperamide Binding to Opiate Receptor Sites of the Brain and Myenteric Plexus", Journal of Pharmacology and Experimental Therapeutics, Vol. 199, No. 1 (1976), pp. 131-140; Stahl, K. D., W. Van Bever, P. Janssen & E. J. Simon, "Receptor Affinity and Pharmacological Potency of a Series of Narcotic Analgesic, Anti-Diarrheal and Neuroleptic Drugs", Eurpoean Journal of Pharmacology, Vol. 46 (1977), pp. 199-205; Wuster, M. & A. Herz, "Opiate Agonist Action of Antidiarrheal Agents In Vitro and In Vivo--Findings in Support for Selective Action", Naunyn-Schmiedeberg's Archives of Pharmacology, Vol. 301 (1978), pp. 187-194; and Giagnoni, G., L. Casiraghi, R. Senini, L. Revel, D. Parolaro, M. Sala & E. Gori, "Loperamide: Evidence of Interaction with .mu. and .delta. Opioid Receptors", Life Sciences, Vol. 33, Suppl. 1 (1983), pp. 315-318. It is generally accepted that mu and/or delta opioid agonists bind to opioid receptors on the presynaptic terminals of peripheral parasympathetic nerves or sensory nerves and inhibit the release of neurotransmitters from these nerve terminals in a number of model systems. See, e.g., Mudge, A. W., S. E. Leeman & G. D. Fischbach, "Enkephaline Inhibits Release of Substance P from Sensory Neurons in Culture and Decreases Action Potential Duration" , Proceedings of the National Academy of Science, USA, Vol. 76, No. 1 (Jan. 1979), pp. 526-530; Frossard, N. & P. J. Barnes, ".mu.-Opioid Receptors Modulate Non-cholinergic Constrictor Nerves in Guinea-Pig Airways", European Journal of Pharmacology, Vol. 141 (1987), pp. 519-522; Burleigh, D. E., "Opioid and Non-opioid Actions of Loperamide on Cholinergic Nerve Function in Human Isolated Colon", European Journal of Pharmacology, Vol. 152 (1988), pp. 39-46; Belvisi, M. G., D. F. Rogers & P. J. Barnes, "Neurogenic Plasma Extravasation: Inhibition by Morphine in Guinea Pig Airways In Vivo", Journal of Applied PhysiologyVol. 66 (1989), pp. 268-272; and Matran, R., C.-R. Martling & J. Lundberg, "Inhibition of Cholinergic and Non-adrenergic, Non-cholinergic Bronchoconstriction in the Guinea Pig Mediated by Neuropeptide Y and .alpha..sub.2 -adrenoceptors and Opiate Receptors", European Journal of Pharmacology, Vol. 163 (1989), pp. 15-23. This inhibition is prevented or reversed by the mu and delta selective opioid antagonist naloxone.
References which disclose the biological and chemical activity of loperamide include the following: Balkovetz, D. F., Y. Miyamoto, C. Tiruppathi, V. B. Mahesh, F. H. Leibach & V. Ganapathy, "Inhibition of Brush-border Membrane Na+-H+ Exchanger by Loperamide", Journal of Pharmacology and Experimental Therapeutics, Vol. 243, No. 1 (Oct. 1987), pp. 150-154; Beubler, E. & P. Badhri, "Comparison of the Antisecretory Effects of Loperamide and Loperamide Oxide in the Jejunum and the Colon of Rats In-vivo", J. Pharm. Pharmacol., Vol. 42 (1990), pp. 689-692; Chang, E. B., D. R. Brown, N. S. Wang & M. Field, "Secretagogue-induced Changes in Membrane Calcium Permeability in Chicken and Chincilla Ileal Mucosa. Selective Inhibition by Loperamide", J. Clin. Invest., Vol. 78, No. 1 (Jul., 1986), pp. 281-287; Haag, K., R. Lubcke, H. Knauf, E. Berger & W. Gerok, "Determination of Rheogenic Ion Transport in Rat Proximal Colon In Vivo", Pflugers Arch., Vol. 405, Suppl. 1 (1985), pp. S67-S70; Hantz, E., A. Cao, R. S. Phadke & E. Taillandier, "The Effect of Loperamide on the Thermal Behavior of Dimyristoylphosphatidylcholine Large Unilamellar Vesicles", Chem. Phys. Lipids (Ireland), Vol. 51, No. 2 (Oct. 1989), pp. 75-82; Hardcastle, J., P. T. Hardcastle & J. Cookson, "Inhibitory Actions of Loperamide on Absorptive Processes in Rat Small Intestine", Gut, Vol. 27, No. 6 (Jun. 1986), pp. 686-694; Hardcastle, J., P. T. Hardcastle & J. Goldhill, "The Effect of Loperamide Oxide on Prostaglandin-Stimulated Fluid Transport in Rat Small Intestine", J. Pharm. Pharmacol., Vol. 42, No. 5 (May, 1990), pp. 364-366; Hardcastle, J., P. T. Hardcastle, N. W. Read & J. S. Redfern, "The Action of Loperamide in Inhibiting Prostaglandin-induced Intestinal Secretion in the Rat", British Journal of Pharmacology, Vol. 74, No. 3 (Nov. 1981), pp. 563-569; Hughes, S., N. B. Higgs & L. A. Turnberg, "Antidiarrhoeal Activity of Loperamide: Studies of its Influence on Ion Transport Across Rabbit Ileal Mucosa In Vitro", Gut, Vol. 23, No. 11 (Nov. 1982), pp. 974-979; Kachur, J. F., D. W. Morgan & T. S. Gaginella, "Effect of Dextromethorphan on Guinea Pig Ileal Contractility In Vitro: Comparison with Levomethorphan, Loperamide and Codeine", Journal of Pharmacology and Experimental Therapeutics, Vol. 239, No. 3 (Dec. 1986), pp. 661-667; Knauf, H. & K. Haag, "Modelling of Colonic Cl.sup.- and K+ Transport Under Resting and Secreting Conditions", Pflugers Arch., Vol. 407, Supplement 2 (1986), pp. S85-S89; Marcais-Collado, H., G. Uchida, J. Costentin, J. C. Schwartz & J. M. Lecompte, "Naloxone-reversible Antidiarrheal Effects of Enkephalinase Inhibitors", European Journal of Pharmacology, Vol. 144, No. 2 (Dec. 1, 1987), pp. 125-132; Marsboom, R., V. Herin, A. Verstraeten, R. Vandesteene & J. Fransen, "Loperamide, a Novel Type of Antidiarrheal Agent. Part 3: In Vitro Studies on the Peristaltic Reflex and Other Experiments on Isolated Tissues", Arzneimittelforschung, Vol. 24, No. 10 (Oct. 1974), pp. 1641-1645; Marsboom, R., V. Herin, A. Verstraeten, R. Vandesteene & J. Fransen, "Loperamide, a Novel Type of Antidiarrheal Agent. Part 4: Studies on Subacute and Chronic Toxicity and the Effect on Reproductive Processes in Rats, Dogs and Rabbits", Arzneimittelforschung, Vol. 24, No. 10 (Oct. 1974), pp. 1645-1649; Megens, A. A., L. L. Canters, F. H. Awouters & C. J. Niemegeers, "Is In Vivo Dissociation Between the Antipropulsive and Antidiarrheal Properties of Opioids in Rats Related to Gut Selectivity? ", Arch. Int. Pharmacodyn. Ther., Vol. 298 (Mar.-Apr., 1989), pp. 220-229; Megens, A. A., L. L. Canters, F. H. Awouters & C. J. Niemegeers, "Normalization of Small Intestinal Propulsion with Loperamide-like Antidiarrheals in Rats", European Journal of Pharmacology, Vol. 178, No. 3 (Mar. 27, 1990), pp. 357-364; Mellstrand, T., "Loperamide--An Opiate Receptor Agonist with Gastrointestinal Motility Effects", Scand. J. Gastroenterol. Suppl., Vol. 130 (1987), pp. 65-66; Miller, R. J., D. R. Brown, E. B. Change & D. D. Friel, "The Pharmacological Modification of Secretory Responses", Ciba Found. Symp., Vol. 112 (1985), pp. 155-174; Nakayama, S., T. Yamasato & M. Mitzutani, "Effects of Loperamide on the Motility of the Isolated Intestine in Guinea Pigs, Rats and Dogs", Niooon Heikatsukin Gakkai Zasshi, Vol. 13, No. 2 (Jun., 1977), pp. 69-74; Niemegeers, C. J., F. M. Lenaerts & P. A. Janssen, "Loperamide, a Novel Type of Antidiarrheal Agent. Part 2: In Vivo Parenteral Pharmacology and Acute Toxicity in Mice. Comparison with Morphine, Codeine and Diphenoxylate", Arzneimittelforschung, Vol. 24, No. 10 (Oct. 1974), pp. 1636-1641; Niemegeers, C. J., F. M. Lenaerts & P. A. Janssen, "Loperamide, a Novel Type of Antidiarrheal Agent. Part 1: In Vivo Oral Pharmacology and Acute Toxicity. Comparison with Morphine, Codeine, Diphenoxylate and Difenoxine", Arzneimittelforschung, Vol. 24, No. 10 (Oct. 1974), pp. 1633-636; Sandhu, B. K., P. J. Milla & J. T. Harries, "Mechanisms of Action of Loperamide", Scand. J. Gastroenterol, Suppl., Vol. 84 (1983), pp. 85-92; Stahl, K. D., W. van Bever, P. Janssen & E. J. Simon, "Receptor Affinity and Pharmacological Potency of a Series of Narcotic Analgesic, Anti-diarrheal and Neuroleptic Drugs", European Journal of Pharmacology, Vol. 46, No. 3 (Dec. 1, 1977), pp. 199-205; Stoll, R., H. Stern, H. Ruppin & W. Domschke, "Effect of Two Potent Calmodulin Antagonists on Calcium Transport of Brush Border and Basolateral Vesicles for Human Duodenum", Ailment. Pharmacol. Ther., Vol. 1, No. 5 (1987), pp. 415-424; Stoll, R., H. Ruppin & W. Domschke, "Calmodulin-mediated Effects of Loperamide on Chloride Transport by Brush Border Membrane Vesicles from Human Ileum", Gastroenterology, Vol. 95, No. 1 (Jul. 1988), pp. 69-76; Turnberg, L. A., "Antisecretory Activity of Opiates In Vitro and In Vivo in Man", Scand. J. Gastroenterol. Suppl., Vol. 84 (1983), pp. 79-83; Turnheim, K., "Antidiarrheal Agents: Tools and Therapeutic Agents", Z. Gastroenterol. (West Germany), Vol. 27, No. 2 (Feb. 1989), pp. 112-119; Verhaeren, E. H., M. J. Dreessen & J. A. Lemli, "Influence of 1,8-Dihydroxyanthraquinone and Loperamide on the Paracellular Permeability Across Colonic Mucosa", J. Pharm. Pharmacol., Vol. 33, No. 8 (Aug. 1981), pp. 526-528; Wehner, F., "Membrane Effects of Loperamide in Absorbing and Secreting Guinea-Pig Gallbladder Epithelium", Naunyn-Schmiedeberg's Archives of Pharmacology, Vol. 335, Supplement (1987), p. R45; Wehner, F., J. M. Winterhager & K. U. Peterson, "Selective Blockage of Cell Membrane K Conductance by an Antisecretory Agent in Guinea-Pig Gallbladder Epithelium", Pfugers Arch. (West Germany), Vol 414, No. 3 (Jul. 1989), pp. 331-339.
Tamaski, J., N. Sakai, K. Isono & T. Takizawa, "Inhibition by Loperamide of Chloride Transport Across Canine Cultured Tracheal Epithelium", European Journal of Pharmacology, Vol. 190 (1990), pp. 255-258, speculates that the inhalation of loperamide could be of value in the treatment of patients with excessive airway surface fluid.
Evidence suggests that sensory C-fiber activation is important in the induction of symptoms associated with rhinitis; see, e.g., Saria, A., "Neuroimmune Interactions in the Airways: lmplications for Asthma, Allergy and Other Inflammatory Airway Diseases", Brain, Behavior, and ImmunityVol 2 (1988), pp. 318-321; Wolf, G. "New Aspects in the Pathogenesis and Therapy of Hyperreactive Rhinopathy", Laryng. Rhinol. Otol., Vol 67 (1988), pp. 438-445; and Stjarne, P., L. Lundblad, J. M. Lundberg & A. Anggard, "Capsaicin and Nicotine-Sensitive Afferent Neurons and Nasal Secretion in Healthy Human Volunteers and in Patients with Vasomotor Rhinitis", British Journal of Pharmacology,. Vol. 96 (1989), pp. 693-710. In respiratory tissue, C-fiber activation causes the local release of inflammatory neuropeptides and also initiates a parasympathetic reflex. Both of these actions produce physiologic changes that can result in the symptoms of rhinorrhea and congestion; see, e.g., Stjarne, et al. and Geppetti, P., B. M. Fusco, S. Marabini, C. A. Maggi, M. Fanciullacci & F. Sicuteri, "Secretion, Pain and Sneezing Induced by the Application of Capsaicin in the Nasal Mucosa in Man", British Journal of Pharmacology, Vol. 93 (1988), pp. 509-514.
It has been reported that the opioid antagonist nalmefene is useful for the treatment of rhinitis; see, e.g., U.S. Pat. No. 4,880,813 issued to Frost on Nov. 14, 1989, and PCT Patent Application Publication No. WO 87/02586 of Key Pharmaceuticals, Inc., inventor: Tuttle, published May 7, 1987.
It is an object of the subject invention to provide novel methods for the treatment of rhinitis.
It is further object of the subject invention to provide novel methods for the topical, intranasal treatment of rhinitis.